Use of sulfamic acids as resolving agent

ABSTRACT

The invention relates to the use of chiral sulfamic acids as resolving agents, the sulfamic acid having the formula (R 1 ,R 2 )N—SO3H, wherein: R 1  and R 2 , being the same or different, represent a hydrogen atom or a C 1 -C 30  linear, branched or cyclic (hetero)-aliphatic or (hetero)-aromatic group, provided that R 1  and R 2  are not both hydrogen and that at least one of the R 1  and R 2  groups is chiral. Further, methods for resolving enantiomeric mixtures are disclosed.

This application is a 371 of PCT/EP02/06321 filed on Jun. 7, 2002.

FIELD OF THE INVENTION

The invention relates to the use of chiral sulfamic acids as resolvingagent for resolving an enantiomeric mixture, in particular a mixture ofbasic enantiomers, and to methods for resolving such enantiomericmixtures.

BACKGROUND OF THE INVENTION

The term “enantiomeric mixture” is known in the art and is understood tomean a mixture of two enantiomers.

The term “resolving enantiomers” is understood in the art to mean theincrease of the relative amount of a particular enantiomer in anenantiomeric mixture. Such a resolving method can be used to obtain anenantiomerically pure compound from an enantiomeric mixture. The term“resolving agent” used herein is understood to mean an agent that can beused for resolving enantiomers.

Resolving methods, known in the art are based on preferentialcrystallisation of diastereomeric salts, formed by a reaction of theresolving agent with the enantiomeric compounds in the mixture.Diastereomeric salts are known to have different physical properties,such as crystallisation characteristics; it is known in the art toseparate diastereomeric salts from one another based on the saiddifferent characteristics, by choosing the proper conditions therefor.Ideally, only the salt of one enantiomeric form of the enantiomericcompound of the mixture precipitates under the chosen conditions,whereas the salts of the other enantiomer remain in solution. Saidprecipitate can be further purified, resulting in an enantiomericallyenriched, or enantiomerically pure compound. Instead of, or in additionto the precipitated fraction, the liquid fraction, the so-called “motherliquor” can be used for the purification of the non-precipitated salt,comprising the antipodic enantiomer of the mixture in enantiomericallyenriched form. Herein, an enantiomer is deemed to be “enantiomericallyenriched” when the said enantiomer is present in a higher molar amountthan the other (antipodic) enantiomer.

Resolution of racemic compounds through formation and separation ofdiastereomeric salts is an important technology for the preparation ofenantiopure products on an industrial scale. The finding of a suitableresolving agent is however, often, trial and error.

In the art, carboxylic acids are known as resolving agents for resolvinga mixture of basic enantiomers; however, such compounds have arelatively weak acidity, resulting in limiting salt formation, which isparticularly problematic for resolving weak basic compounds.

Further, 10-camphorsulfonic acid is known as resolving agent for basicenantiomeric mixtures, see Stereochem. Org. Compounds, E. L. Eliel, S.H. Wilen, Wiley Interscience, N.Y., U.S.A., 1994, pp. 322-337. However,the diversity in resolving agents, in particular in resolving weak basicenantiomers, in limited.

SUMMARY OF THE INVENTION

According to the invention, it is now found that chiral sulfamic acidshaving an enantiomeric purity of at least 90% of formula (I):(R₁,R₂)N—SO₃H  (I)wherein:

R₁ and R₂, being the same or different, are selected from the groupconsisting of:

-   a hydrogen atom,-   a linear, branched or cyclic alkyl or heteroalkyl group, being    optionally substituted, or-   an aromatic or heteroaromatic group, being optionally substituted,    provided that R₁ and R₂ are not both hydrogen and that at least one    of the R₁ and R₂ groups is chiral, have optimal and surprising    properties rendering these compounds highly suitable for use as    resolving agent for resolving a mixture of enantiomers, resulting in    efficient resolution of mixtures of enantiomeric compounds.

The said sulfamic acids have a stronger acidity than correspondingcarboxylic acids and will therefore have an increased potency for saltformation, particularly with weakly basic compounds. Thus the currentmethod provides a significant enhancement in diversity.

DETAILED DESCRIPTION OF THE INVENTION

The term “enantiomeric purity of at least 90%” means that, on a molarbasis, at least 95% of the sulfamic acid has the same stereochemicconformation; this means that less than 5% of the sulfamic acid is ofthe antipodic stereochemic conformation. This can be derived from theknown formula for enantiomeric purity[(A−B)/(A+B)]×100%,wherein A and B stand for each of the enantiomers respectively. It is tobe noted that the maximum obtainable resolution of the enantiomers inthe mixture corresponds to the enantiomeric purity of the resolvingagent; this means that when the resolving agent has an enantiomericpurity of 95%, the maximum obtainable resolution of the enantiomers willbe 95%.

Sulfamic acids as such and the preparation thereof from amines are knownin the art; U.S. Pat. No. 2,933,513 describes the preparation of (saltsof) testosterone sulfamic acids. These compounds are used aswater-soluble analogues of testosterone. A. G. Lloyd, et al.(Biochemical Journal 92, 1964, 68-72) discloses the synthesis of labeledsulfamic acids of D-glucosamine for metabolism studies. S.-K. Chung, etal. (Tetrahedron 54, 1998, 15899-15914) describe the synthesis ofsulfamic acid steroid derivatives for use as antifungal agents. M. L.Wolfrom, et al. (Journal of the American Chemical Society 79, 1957,5043-5046) disclose the synthesis of D-glucose derivatives containing asulfamic acid group by reaction of D-glucosamine free base withSO₃-pyridine complex. This unit is present in heparin. M. H. Payne, etal. (Journal of Medicinal Chemistry 34, 1991, 1184-1187) describe theeffect of sulfation in hirudin and hirudin PA related anticoagulantpeptides as part of a structure activity relationship (SAR) study. Also,the synthesis of sulfamic acid derivatives of these peptides is given.R. Crosstick, et al. (Tetrahedron 40, 1984, 427-431) describe thesynthesis of nucleoside analogues acting as antimetabolites (e.g.antiviral agents). One of the synthesised compounds is a sulfamic acidprepared from an amine and SO₃-triethylamine complex. I. Marle, et al.(Journal of Chromatography 586, 1991, 223-248) disclose a new chiralstationary phase for high-performance liquid chromatography based oncellulase. One of the solute structures is alfa-phenylethyl sulfamicacid. B. M. Kim, et al. (Tetrahedron letters 39, 1998, 5381-5384)describe new hydrolysis conditions for alfa-aminosulfamic acids,resulting in the formation of chiral diamines. These compounds areimportant building blocks in the synthesis of enzyme inhibitors. S. B.Cohen, et al. (Organic Letters 3, 2001, 405-407) present the synthesisof S-linked glycoconjugates via opening of a cyclic sulfamidate with1-thio sugars and hydrolysis of the resulting sulfamic acids. J. E.Baldwin, et al. (Tetrahedron Asymmetry 1, 1990, 881-884) describe thenucleophilic opening of cyclic sulfamidates and subsequent hydrolysis ofthe in situ formed sulfamic acid is described.

When the sulfamic acid comprises, as R1 or R2, or both, an alkyl group,the alkyl group is preferably C₁-C₃₀ alkyl group; if the said alkylgroup comprises a hetero atom, the said hetero atom is preferablyselected from N, P, O and S.

When the sulfamic acid comprises, as R1 or R2, or both, an aromatic orheteroaromatic group, the said group preferably has 3-30 C-atoms; incase the said aromatic group is a heteroaromatic group, the hetero atomis preferably selected from N, P, O and S.

It is nevertheless observed that the above enumerations are notlimitative; R₁ and R₂ can also represent other groups, provided that thesulfamic acid is still chiral.

Preferably, the sulfamic acid has an enantiomeric purity of at least95%, more preferably of at least 99% or more. Most preferably, thesulfamic acid is homochiral. As outlined above, the resolution of theenantiomers in the mixture is dependent on the enantiomeric purity ofthe resolving agent; therefore, it is highly preferred for the sulfamicacid to be as enantiomerically (i.e. chirally) pure as possible.

As the salt formation of the sulfamic acid an the enantiomers in themixture is an acid-base reaction, the enantiomers in the mixture to beresolved are preferably basic enantiomers. The enantiomers should atleast be capable of being susceptible to an acid-base reaction withsulfamic acid to form the diastereomeric salts. The basic enantiomersare preferably amines.

According to the invention sulfamic acid can be used advantageously toresolve both racemic and non-racemic mixtures, e.g. wherein the molarratio between both enantiomers is 1:10.

The invention further relates to a method for resolving a mixture ofenantiomers B, comprising the steps of:

-   a) reacting in a liquid medium said mixture with a chiral sulfamic    acid having an enantiomeric purity of at least 90% of formula (I):    (R₁,R₂)N—SO₃H  (I)-    as defined above, to obtain diastereomeric salts of formula (IV):

-    resulting in preferential crystallization of either the p- or the    n-diastereomeric salt,-   b) recovering the crystallized salt obtained in step a),-   c) treating the recovered crystallized salt of b) with a base to    obtain the compound B in an enantiomerically enriched form, and,    optionally,-   d) recovering the sulfamic acid from c).

This process is schematically represented as follows:

According to the above method, enantiomeric mixtures can be resolved viaintermediacy of sulfamate formation; in step a), the enantiomericmixture is reacted with a sulfamic acid forming diastereomeric sulfamatesalts through an acid-base reaction. Proper reaction conditions areknown in the art; any skilled person will be aware of finding theconditions to conduct such a reaction. By this reaction, the p- orn-form of the diastereomeric salts crystallise and precipitatepreferentially, as is outlined above, therewith leaving the remainingenantiomeric form, the antipode, in solution. The skilled person will beaware of suitable reaction conditions to obtain the envisagedpreferential crystallisation. Subsequently, the crystallised salt isrecovered from the mixture by purification methods, known in the art.The recovered crystallised salt comprises the required enantiomer inenriched form. To obtain the enantiomer in the original form, the saltis treated with a base, so that the original enantiomer is released. Itis to be understood that hereto, the said base should preferably be astronger base than the enantiomer in the salt. Said enriched enantiomercan be further purified as known in the art. Optionally, the sulfamicacid is recovered from the mixture by e.g. acidification of the mixture;an example of a suitable recovery is by ion exchange and subsequentfreeze drying. The recovered sulfamic acid can be reused.

It is also possible to recover the envisaged enantiomer from the motherliquor, in case the salt of the said enantiomer remains in solution, andthe salt of the antipode crystallises. In such a case, the mother liquoris enantiomerically enriched by removal of the precipitated crystals ofthe salt of the antipode. If both enantiomers are to be purified, boththe salt crystals and the solubilised salt can be used for furtherpurification of the respective enantiomers. Thus, in addition to orinstead of steps b) and c) the diastereomeric salts from the liquid canbe recovered and treated with a base to obtain compound B in anenantiomerically enriched form.

In order to obtain optimal resolution, as outlined above, the sulfamicacid has an enantiomeric purity of least 90%, preferably at least 95%,more preferably at least 99% or more and most preferably beinghomochiral. The best resolution is obtained when the sulfamic acid is aschirally pure as possible.

Preferably, as outlined above, the enantiomers B are basic enantiomers,preferably amines.

In a very special embodiment of the invention, the enantiomericcompounds of the mixture are amines, and the (R₁,R₂)N-moiety of thesulfamic acid used as resolving agent is stereochemically identical tothe (R₁,R₂)N-moiety of one of the amines of the enantiomeric mixture.This is particularly advantageous when the n-salt of the sulfamic acidand the enantiomer crystallises. In that case, the crystallised saltconstitutes of two chirally identical amine moieties that both can bepurified; first, the n-salt is treated with a base as outlined above,resulting in release of the envisaged enantiomeric amine; second, thesulfamic acid can be recovered and treated, e.g. with an acid, to removethe SO₃ moiety therefrom resulting in stereochemically the same amine asreleased from the salt, therewith duplicating the yield. Thus, thepurified product originates both from the enantiomeric mixture and fromthe resolving sulfamic acid. As outlined above, it is also possible toobtain the envisaged enantiomer in case the n-salt remains in solution,by recovering the said salt from the solution. Thereto, the mixture ofbasic enantiomers comprise an enantiomeric mixture of amines of formula(II):(R₁,R₂)N—H  (II),wherein R1 and R2 are as above, and wherein the (R₁,R₂)N-moiety of thesulfamic acid of step a) is identical to at least one of the amines inthe said enantiomeric mixture; in that case, “B” in the above scheme is

Very interestingly, it has also been found that the use of sulfamic acidas resolving agent enables the resolution of enantiomeric mixtures ofamines of formula (II), as defined above, by first converting the saidamines in an enantiomeric mixture of sulfamic acids, and by subsequentresolution of the thus formed enantiomeric sulfamic acid mixture with asuitable basic resolving agent; thereto the invention provides a methodfor resolving an enantiomeric mixture of amines of formula (II):(R₁,R₂)N—H  (II)wherein R₁ and R₂ are as defined above, comprising the steps of:

-   1) reacting the said amines with a suitable reagent to obtain an    enantiomeric mixture of corresponding sulfamic acid having    formula (I) as defined above,-   2) reacting the sulfamic acid of step 1) with a chiral basic    resolving agent A having an enantiomeric purity of at least 90% to    obtain diastereomeric salts of formula (V)

-    resulting in preferential crystallisation of either the p- or the    n-diastereomeric salt,-   3) recovering the crystallised salt obtained in step 2),-   4) treating the recovered crystallised salt of step 3), with an acid    to obtain the sulfamic acid of formula (I) in an enantiomerically    enriched form,-   5) recovering the amine of formula (II) from the sulfamic acid    obtained in step 4) by removal of SO₃, and, optionally,-   6) recycling the resolving agent A from step 4).

The above method is illustrated in the reaction scheme below:

Virtually all commercially available chiral amines can be used in theabove process, for example, (R)-1-(4-nitrophenyl)ethylaminehydrochloride, (+)-dehydroabiethylamine, (S)-2-amino-1,1-diphenylpropanol, D-phenylalaninol, L(−)-α-amino-ε-caprolactam,(R)-(−)-1-amino-2-propanol, (R)-(+)-1-(1-naphthyl)ethylamine,(R)-(+)-1-(2-naphthyl)ethylamine, (R)-(+)-1-(4-bromophenyl)ethylamine,(R)-(+)-α-methylbenzylamine, (S)-(−)-1-(1-naphthyl)ethylamine,(S)-(−)-1-(2-naphthyl)ethylamine, (S)-(−)-1-(4-bromophenyl)ethylamine,(S)-(−)-α-methylbenzylamine, (S)-(+)-1-amino-2-propanol,(R)-(+)-bornylamine, (R)-(−)-phenylglycinol, (S)-(+)-phenylglycinol,D-(+)-phenylalaninol, L-(−)-phenylalaninol,(1S,2S)-(+)-2-amino-3-methoxy-1-phenyl-1-propanol,(−)-cis-myrtanylamine, D-(+)-norephedrine, L-(−)-norephedrine,(1R,2R)-(−)-2-amino-1-phenyl-1,3-propanediol,(1S,2S)-(+)-2-amino-1-phenyl-1,3-propanediol, (R)-(−)-1-aminoindan,(S)-(+)-1-aminoindan, (−)-isopinocamphenylamine,(+)-isopinocamphenylamine, (1R,2S)-(−)-cis-1-amino-2-indanol,(1S,2R)-(+)-cis-1-amino-2-indanol, (S)-2-phenylglycine methyl esterhydrochloride, (S)-2-phenylglycine methyl ester hydrochloride,(−)-L-phenylalanine benzyl ester, (R)-1-(3-methoxyphenyl)ethylamine,(S)-1-(3-methoxyphenyl)ethylamine, (R)-1-(4-methoxyphenyl)ethylamine,(S)-1-(4-methoxyphenyl)ethylamine,(1R,2S)-(+)-cis-[2-(benzylamino)cyclohexyl]methanol,(−)-bis[(S)-1-phenylethyl amine hydrochloride, (−)-ephedrine,(+)-bis-[(R)-1-phenylethyl]amine hydrochloride, (+)-ephedrinehydrochloride, (1S,2R)-(−)-cis-[2-(benzylamino)cyclohexyl]methanol,(R)-benzyl-1-(1-naphthyl)ethylamine hydrochloride,(S)-1-(4-nitrophenyl)ethylamine hydrochloride,(S)-benzyl-1-(1-naphthyl)ethylamine hydrochloride,(R)-(+)-N-benzyl-1-phenylethylamine,(R)-(+)-N-methyl-1-phenylethylamine, (1R,2S)-(−)-N-methylephedrine,brucine, quinine, (−)-strychnine, cinchonidine, cichonine, quinidine,(R)-(+)-N,N-dimethyl-1-phenylethylamine,(S)-(−)-N,N-dimethyl-1-phenylethylamine, D-arginine, D-aspartic acid,D-glutamic acid, D-valine, L-aspartic acid, L-glutamic acid, L-valine.

Preferably, the suitable reagent to be used in the above process, ischlorosulfonic acid, sulfur trioxide, adducts of sulfur trioxide, suchas in particular sulfur trioxide pyridine complex, sulfur trioxidedimethylformamide complex; also virtually any other adduct of sulfurtrioxide can be used for the preparation of the envisaged sulfamicacids.

Because many starting amines are inexpensive reagents, and for theconversion thereof to sulfamic acids inexpensive reagents can be used, abasis for the large-scale use of sulfamic acids in diastereomer mediatedresolutions is provided. The skilled person is aware of suitablereaction conditions for the preparation of the envisaged sulfamic acids.

Suitable basic resolving agents are known in the art, and can e.g. bechosen from the above-mentioned list of chiral amines.

In step 4), an acid should be used that is stronger than the sulfamicacid of the crystallised salt.

Treatment of a sulfamic acid to obtain the corresponding amine, theabove step 5), are known in the art; preferably, step 5) comprisestreatment of the sulfamic acid with chemical or thermal means,preferably by treatment with a hydrohalogenic acid, preferablyhydrochloric acid. Steps 4) and 5) may preferably be combined by asingle acid treatment. In addition to the above acids, the skilledperson will be aware of suitable acids, such as e.g. sulfuric acid andnitric acid.

As outlined above, it is also possible to recover the envisagedenantiomer from the mother liquor, in case the salt of the saidenantiomer remains in solution, and the salt of the antipodecrystallises. In such a case, the mother liquor is enantiomericallyenriched by removal of the precipitated crystals of the salt of theantipode. If both enantiomers are to be purified, both the salt crystalsand the solubilised salt can be used for further purification of therespective enantiomers. Thus, in addition to or instead of steps 3) and4) the diastereomeric salts from the liquid can be recovered and treatedwith an acid to obtain the sulfamic acid in an enantiomerically enrichedform.

In a very special embodiment of the invention, the basic resolving agentis an amine, having a (R₁,R₂)N— moiety being stereochemically identicalto the (R₁,R₂)N— moiety of one of the sulfamic acid enantiomers of theenantiomeric mixture. This is particularly advantageous when the n-saltof the sulfamic acid enantiomer and the resolving amine crystallises. Inthat case, the crystallised salt constitutes of two chirally identicalamine moieties that both can be purified; first, the n-salt is treatedwith an acid as outlined above, resulting in release of the envisagedenantiomeric sulfamic acid; the amine is subsequently released from thesaid sulfamic acid by removal of the SO₃ moiety therefrom, e.g. with anacid. Second, the resolving amine, being stereochemically identical tothat of the said sulfamic acid is recovered from the salt, resulting induplication of the yield. Thus, the purified product originates bothfrom the enantiomeric sulfamic acid mixture and from the resolvingamine. As outlined above, it is also possible to obtain the envisagedenantiomer in case the n-salt remains in solution, by recovering thesaid salt from the solution. Thus, the basic resolving agent Apreferably comprises an enantiomer of the amines to be resolved, whichamines are first converted to the corresponding sulfamic acid.

According to the method according to the invention, it is also possibleto resolve an enantiomeric mixture of sulfamic acids, without firstconverting an amine into the corresponding sulfamic acid; in that case,any enantiomeric mixture of sulfamic acids may be used and resolved(i.e. be enriched in one of the enantiomers of the mixture). Also, afurther removal of SO₃ from the obtained enantiomerically enrichedsulfamic acid is not necessary. Thus, the above steps 1) and 5) are notperformed according to this embodiment of the invention.

As outlined above, it is highly preferred to use a resolving agent thatis chirally as pure as possible, resulting in chirally highly enrichedenantiomers, or even to chirally pure enantiomers (i.e. having a chiralpurity of 95-100%, preferably 99-100%). Thereto, the resolving agent hasan enantiomeric purity of at least 90%, preferably of at least 95%, morepreferably of at least 99%; the resolving agent is most preferablyhomochiral.

Preferably, the molar ratio of the resolving agent:enantiomers in themixture is substoichiometric and preferably 0.5 eq, as explained by Popeand Peachey in their method of half quantities, and disclosed inEnantiomers, Racemates and Resolutions, Wiley and Sons, New York (1981),pp. 309-313, herein incorporated by reference.

In an attractive embodiment of the invention, the enantiomeric mixtureto be resolved is preferably a racemic mixture, in particular whensubstoichiometric amounts of resolving agent are used (see Pope andPeachy, supra).

The invention is now further illustrated by non-limitative examples.

EXAMPLE 1 Preparation of D-phenylalaninol sulfamic acid

500 mg (3.31 mmol) D-phenylalaninol was dissolved in 10 ml ofdemi-water. The pH of the mixture was adjusted to pH 9.5-10.0 viaaddition of an aqueous 1.0 N NaOH solution. 659 mg (3.64 mmol) of sulfurtrioxide pyridine complex was added in small portions over a period of0.5 h with constant addition of 1.0 N NaOH solution to maintain a pH of9.5-10.0. After the reaction was complete the reaction mixture wasconcentrated to remove the pyridine. Ethanol was added and the formedprecipitate was removed by filtration and discarded. Acetone was addedand the product precipitated from the solution. Filtration yielded 537mg (2.32 mmol) of the sodium salt of D-phenylalaninol sulfamic acid(70%).

Next, 92 mg (0.36 mmol) of the sodium salt of D-phenylalaninol sulfamicacid was dissolved in 5 ml demineralized water. 3 ml of a suspension ofDowex-H⁺ in demineralized water was added and stirred for 5 min. Themixture was filtered, the resin was rinsed 4 times with 5 ml ofdemineralized water and the collected aqueous filtrate was freeze-dried.85 mg (0.36 mmol) of D-phenylalaninol sulfamic acid was obtained afterfreeze-drying.

EXAMPLE 2 Resolution of racemic α-methylbenzylamine

80 mg (0.34 mmol) of D-phenylalaninol sulfamic acid was dissolved in 15ml ethanol after which 43 mg (0.35 mmol) of racemic α-methylbenzylaminedissolved in 2 ml ethanol was added. The solvent was evaporated to atotal volume of 3 ml and cooled down to accelerate crystallisation.After crystallisation both mother liquor and crystals were analysed byHPLC on a chiral ODH-column (eluent hexane: isopropylalcohol 90:10) todetermine the relative amount of (S)- and (R)-α-methylbenzylamine. HPLCanalysis showed enantiomeric enrichment of both the crystals and themother liquor.

EXAMPLE 3 Preparation of (D)-1-(-3-methoxyphenyl)ethyl sulfamic acid andresolution of racemic α-methylbenzylamine

1.17 g (7.73 mmol) (D)-1-(-3-methoxyphenyl)ethyl amine was addeddropwise to a suspension of 1.32 g (8.63 mmol) sulfur trioxideN,N-dimethylformamide complex in 15 ml of THF. After stirring for 10min. TLC-analysis showed complete disappearance of primary amine(ninhydrine colouring). After evaporation of the solvents the sulfamicacid was obtained as a clear oil.

87 mg (0.38 mmol) of the sulfamic acid of (D)-1-(-3-methoxyphenyl)ethylamine was dissolved in 1 ml of acetone and 48 mg (0.40 mmol) of racemicα-methylbenzylamine in 1 ml acetone was added. Within an hour crystalswere formed and HPLC analysis showed enantiomeric enrichment of both thecrystals and the mother liquor.

1. A method for resolving an enantiomeric mixture of enantiomers B,wherein enantiomers B are basic enantiomers mixture of amines of formula(II),(R1,R2)N—H  (II) comprising the steps of: a) reacting in a liquid mediumsaid enantiomeric mixture of basic enantiomers with a chiral sulfamicacid having an enantiomeric purity of at least 90% of formula (I):(R1,R2)N—SO3H  (I) wherein: R1 and R2, being the same or different, areselected from the group consisting of: hydrogen, a linear, branched orcyclic alkyl or heteroalkyl group, being optionally substituted, or anaromatic, being optionally substituted, provided that R1 and R2 are notboth hydrogen and that at least one of the R1 and R2 groups is chiral,to obtain diastereomeric salts of formula (IV):

 wherein B is enantiomers mixture of amines of formula (II), resultingin preferential crystallization of either the p- or the n-diastereomericsalt, b) recovering the crystallized salt obtained in step a), c)treating the recovered crystallized salt of b) with a base to obtain theenantiomers B in an enantiomerically enriched form, and, optionally, d)recovering the sulfamic acid from c).
 2. The method according to claim1, wherein in addition to or instead of steps b) and c) thediastereomeric salts from the liquid are recovered and treated with abase to obtain enantiomers B in an enantiomerically enriched form. 3.The method according to claim 2, wherein the sulfamic acid has anenantiomeric purity of at least 95%, and most preferably of at least 99%or more.
 4. The method according to claim 1, wherein the mixture ofenantiomers B is an enantiomeric mixture of amines of formula (II):(R1,R2)N—H  (II), wherein R1 and R2, being the same or different, areselected from the group consisting of: hydrogen, a linear, branched orcyclic alkyl or heteroalkyl group, being optionally substituted, or anaromatic group, being optionally substituted, provided that R1 and R2are not both hydrogen and that at least one of the R1 and R2 groups ischiral, and wherein the (R1,R2)N— moiety of the sulfamic acid of step a)is identical to at least one of the amines in the said enantiomericmixture.
 5. Method according to claim 4, further comprising step: e)removing the SO₃ moiety of the sulfamic acid, recovered in step d) toobtain the amine of formula (II).
 6. A method for resolving anenantiomeric mixture of amines of formula (II):(R1,R2)N—H  (II) wherein R1 and R2, being the same or different, areselected from the group consisting of: hydrogen, a linear, branched orcyclic alkyl or heteroalkyl group, being optionally substituted, or anaromatic group, being optionally substituted, provided that R1 and R2are not both hydrogen and that at least one of the R1 and R2 groups ischiral, comprising the steps of: 1) reacting the said amines with asuitable reagent to obtain an enantiomeric mixture of correspondingsulfamic acid having formula (I):(R1,R2)N—SO3H  (I) wherein: R1 and R2, being the same or different, areselected from the group consisting of: hydrogen, a linear, branched orcyclic alkyl or heteroalkyl group, being optionally substituted, or anaromatic group, being optionally substituted, provided that R1 and R2are not both hydrogen and that at least one of the R1 and R2 groups ischiral, 2) reacting in a liquid medium the sulfamic acid of step 1) witha chiral basic resolving agent A having an enantiomeric purity of atleast 90% to obtain diastereomeric salts of formula (V)

 resulting in preferential crystallization of either the p- or then-diastereomeric salt, 3) recovering the crystallised salt obtained instep 2), 4) treating the recovered crystallised salt of step 3), with anacid to obtain the sulfamic acid of formula (I) in an enantiomericallyenriched form, 5) recovering the amine of formula (II) from the sulfamicacid obtained in step 4) by removal of SO₃, and, optionally, 6)recovering the resolving agent A from step 4).
 7. The method accordingto claim 6, wherein in addition to or instead of steps 3) and 4) thediastereomeric salts from the liquid are recovered and treated with anacid to obtain the sulfamic acid in an enantiomerically enriched form.8. The method according to claim 6, wherein the reagent of step 1)comprises chlorosulfonic acid, sulfur trioxide, adducts of sulfurtrioxide, sulfur trioxide pyridine complex, sulfur trioxidedimethylformamide complex or a combination of two or more thereof. 9.The method according to any of the claim 5, wherein step e) comprisestreatment of the sulfamic acid with chemical or thermal means.
 10. Themethod according to any of the claim 6, wherein the basic resolvingagent A comprises an enantiomer of the amines to be resolved.
 11. Themethod for the resolution of an enantiomeric mixture of sulfamic acidshaving formula (I) as defined in claim 6, comprising steps 2), 3), 4)and optionally step 6) of claim
 12. 12. The method according to claim 1,wherein the resolving agent has an enantiomeric purity of at least 95%.13. The method according to claim 1, wherein the molar ratio ofresolving agent:entantiomers in the mixture to resolving agent is usedin a substoichiometric amount and most preferably at 0.5 eq.
 14. Themethod according to claim 1, wherein the mixture of enantiomers is aracemic mixture.
 15. The method according to claim 5, wherein step e)comprises treatment of the sulfamicacid with a hydrohalogenic acid. 16.The method according to claim 6, wherein step 5 comprises treatment ofthe sulfamic acid with chemical or thermal means.
 17. The methodaccording to claim 6, wherein step 5 comprises treatment of thesulfamicacid with a hydrohalogenic acid.
 18. The method according toclaim 6, wherein the resolving agent A has an enantiomeric purity of atleast 99%.
 19. The method according to claim 1, wherein the sulfamicacid has an enantiomeric purity of at least 99%.
 20. The methodaccording to claim 6, wherein the molar ratio of resolving agent A:entantiomers in the mixture to resolving agent is used in asubstoichiometric amount and most preferably at 0.5 eq.
 21. The methodaccording to claim 6, wherein the mixture of enantiomers is a racemicmixture.